Isolated tuberculous monoarthritis mimicking oligoarticular juvenile rheumatoid arthritis

Isolated monoarthritis caused by Mycobacterium tuberculosis in the absence of clinical pulmonary disease is extremely rare in North America. After decades of consistent declines in incidence, a remarkable resurgence of tuberculosis (TB) is occurring in North America. It must always be considered in the differential diagnosis of chronic monoarthritis if devastating sequelae are to be avoided. We describe 2 cases of tuberculous arthritis in young children presenting with monoarthritis of the knee. The presumptive diagnosis in each case was oligoarticular onset juvenile rheumatoid arthritis (JRA). Each had an atypical course for JRA, with lack of response to intraarticular corticosteroid. The diagnosis of TB arthritis was made only with synovial biopsy.     

CASE REPORT: TUBERCULOUS ARTHRITIS OF PERIPHERAL JOINTS IN PATIENTS WITH PREVIOUS INFLAMMATORY RHEUMATIC DISEASE

Four patients with a previous inflammatory rheumatic diseasedeveloped a peripheral tuberculous (TB) arthritis in a jointapparently affected by a rheumatic disease. The single mostimportant factor in the diagnosis of TB was the presence ofpast or present pulmonary TB or a family history on a backgroundof steroid use. Clinical presentation, disease evolution, androutine laboratory tests were unhelpful. The most effectivemethod of diagnosis was synovial biopsy. KEY WORDS: Mycobacterium, Infection, Steroids, Gout, SLE, Polyarthritis     

Mimicry of lyme arthritis by synovial hemangioma

To report on the differential diagnosis of lyme arthritis and synovial hemangioma due to similar clinical and radiological signs and symptoms. A 15-year-old boy presented at the age of 9 with recurrent rather painless swelling of the right knee. Altogether four episodes lasting for 1–2 weeks each occurred over a period of 18 months before medical advice was sought. Physical examination revealed only a slightly limited range of motion. Living in an endemic area of borreliosis, he reported a tick bite 6 months prior to onset of his symptoms with erythema migrans and was treated for 10 days with amoxicillin. Serology revealed two positive unspecific bands in IgG immunoblot (p41 and 66) with slight positivity for ELISA. Ultrasound revealed synovial thickening and increased fluid. Despite the weak positive serology a diagnosis of lyme arthritis could not be excluded and intravenous antibiotic treatment with ceftriaxone was started. After two further relapses antiinflammatory therapy including intraarticular steroids were introduced with no long lasting effect. A chronical disease developed with alternate periods of swelling and almost complete remission. Ultrasound as well as MRI demonstrated ongoing signs of synovitis, therefore after further progression, a diagnostic arthroscopy was performed showing an inconspicuous knee joint. A second MRI showed focal suprapatellar enhancement and was followed by open arthrotomy revealing a histopathological proven synovial cavernous juxtaarticular hemangioma. To our knowledge, the differential diagnosis of lyme arthritis and synovial hemangioma has not yet been reported despite obvious clinical similarities. In conclusion, in children and adolescents synovial hemangioma has to be considered in differential diagnosis of recurrent knee swelling. Early diagnosis is important to prevent prolonged suffering from chronic joint swelling with probable joint damages, unnecessary treatment procedures and as well school and sports absenteeism.     

Intestinal tuberculosis. A diagnostic challenge

Tuberculosis (TB) is a common disease in Spain, whose incidence has increased due to AIDS, immunotherapy and immigration. Intestinal disease is rare and can be difficult to diagnose because its symptoms and laboratory results are nonspecific. In addition, endoscopic lesions resemble those of other diseases such as Crohns disease (CD). Differentiating between intestinal TB and CD is very important since steroid treatment con be life saving in CD and lethal in intestinal TB. Colonoscopy plays an important role in establishing a suspected diagnosis. The endoscopic findings most characteristic of intestinal TB are circular ulcers, small diverticula (3-5 mm), and sessile firm polyps. The suspected diagnosis must be confirmed by the presence of caseating granulomas and/or acid fast bacilli. Polymerase chain reaction is currently recommended for assessing the presence of tubercle bacilli in tissue specimens obtained by endoscopic biopsy. We report a case of intestinal TB in a female renal transplant recipient that demonstrates the difficulty of making this diagnosis.     

Synovial fluid and serum concentrations of aminoterminal propeptide of type III procollagen in healthy volunteers and patients with joint disease.

OBJECTIVES--To analyse synovial fluid and serum concentrations of the amino-propeptide of the type III procollagen (PIIINP) in normal individuals and patients with joint disease, and to explore the relationship between synovial fluid PIIINP concentrations and the rheumatological diagnosis, local inflammation, and joint disease. METHODS--A radioimmunoassay was used to measure the PIIINP concentrations in serum and knee joint synovial fluid from 16 healthy volunteers and patients with osteoarthritis (OA) (n = 40), rheumatoid arthritis (RA) (n = 30), and psoriatic arthritis (PsA) (n = 12). The PIIINP measurements were related to demographic data, synovial fluid leucocyte counts, and radiographic changes at the knee. RESULTS--Serum PIIINP concentrations were greater in each of the disease groups than in control subjects, but there were no differences between the disease groups. Synovial fluid concentrations of PIIINP were much greater than those in serum, indicating local production, and were significantly greater in RA than in other disease groups (p < 0.001). There was only a weak positive correlation between synovial fluid leucocyte counts, some radiographic changes, and synovial fluid PIIINP concentrations. CONCLUSIONS--These data suggest that synovial fluid PIIINP concentrations may reflect local synovial proliferative processes in joint disease, and that they could be of diagnostic and prognostic value in inflammatory arthropathies.     

Synovial lipoma arborescens

Synovial lipoma arborescens is a rare and benign intra-articular pathology, of unknown etiology, characterized by a villous and lipomatous proliferation of synovial tissue. It presents with atypical clinical manifestations, usually located in the knee, represented as recurrent joint effusions and painless swelling joint. The magnetic resonance is the most specific test and can often even avoid the synovial biopsy. We related the case of a female patient with mechanical pain in the knee with indolent evolution for 18 years, clinical and radiological compatible with osteoarthritis. With the finding of a localized unilateral increase of the suprapatellar bursa without perceptible joint effusion and ultrasonographic aspect of an exuberant nodular synovitis, the possibility of villonodular pigmented synovitis had to be discarded by synovial biopsy. Even after this procedure, her diagnosis was not clear, being reported to rheumatology evaluation due to histopathology findings confused with rheumatoid arthritis. The set of clinical, laboratory, magnetic resonance and histological review of synovial tissue confirmed the diagnosis of synovial lipoma arborescens, excluding the possibility of rheumatoid arthritis.     

POPLITEAL CYSTS AND SYNOVIAL RUPTURE IN OSTEOARTHROSIS

The range of symptomatology produced by synovial protrusionsin degenerative disease of the knee joint is demonstrated infive representative case histories. The most common mechanismis the formation of a popliteal cyst, which may be asymptomaticor painful. It may be in free communication with the knee jointor only fill after exercise. Rupture of the knee joint can occur,but the clinical picture is much less dramatic than with inflammatoryjoint disease. This is related to the less irritative characterof osteoarthritic synovial fluid. The diagnosis is proved byarthrography, which is an easy and relatively painless procedure,but it is important that a post-exercise film is taken. Healingof the rupture site may occur rapidly, as shown in one case. ^*Present address: Kantonssopital Zurich, Switzerland.     

Primary Neisseria meningitidis arthritis of the knee without meningitis: contribution of synovial fluid culture in blood-culture vial

INTRODUCTION: Primary meningococcal arthritis is a rare form of meningococcal disease. It occurs as an isolated acute purulent arthritis without meningitis, and presence of Neisseria meningitidis in articular fluid. We report a new case of typical primary meningococcal arthritis. EXEGESIS: A previously healthy 23-year-old female patient was admitted for purpuric lesions of the legs. At admission, conscience was normal and symptoms of meningitis were absent. During the 2nd day of hospitalisation, a warm and painful effusion in the right knee appeared. Aspiration from the right knee yielded a purulent fluid. N. meningitidis was isolated from a blood-culture vial inoculated with the synovial fluid, while blood cultures remained sterile. Anti-biotherapy was initiated as soon as microbiological diagnosis was established. The patient was symptom-free 1 month later. CONCLUSION: We emphasize the fact that agar cultures of the synovial fluid remained sterile, while N. meningitidis grew in a blood-culture vial. We suggest that diagnosis of primary meningococcal arthritis may be underestimated when inappropriate culture media are used.     

Epidemiology of septic arthritis of the knee at Hospital das Clínicas,Universidade de São Paulo

BackgroundSeptic arthritis is an infrequent disease although very important due to the possibility of disastrous outcomes if treatment is not adequately established. Adequate information concerning the epidemiology of septic arthritis is still lacking due to the uncommon nature of the disease as well as the struggle to establish a correct case-definition.ObjectiveTo epidemiologically characterize the population seen at Hospital das Clínicas, University of São Paulo with a diagnosis of septic arthritis between 2006 and 2011.MethodsSixty-one patients diagnosed with septic arthritis of the knee between 2006 and 2011 were retrospectively evaluated. The patients’ clinical and epidemiological characteristics, the microorganisms that caused the infection and the patients’ treatment and evolution were analyzed.ResultsSeptic arthritis of the knee was more common among men, with distribution across a variety of age ranges. Most diagnoses were made through positive synovial fluid cultures. The most prevalent clinical comorbidities were systemic arterial hypertension and diabetes mellitus, and the most commonly reported joint disease was osteoarthritis. Staphylococcus aureus was the prevailing pathogen. Fever was present in 36% of the cases. All patients presented elevation in inflammatory tests. Gram staining was positive in only 50.8% of the synovial fluid samples analyzed. Six patients presented complications and unfavorable evolution of their condition.ConclusionS. aureus is still the most common pathogen in acute knee infections in our environment. Gram staining, absence of fever and normal leukocyte count cannot be used to rule out septic arthritis.     

Synovial fluid adenosine deaminase activity to diagnose tuberculous septic arthritis

There are reports of a correlation between high adenosine deaminase (ADA) levels in body fluid and tuberculosis (TB) infection, but none have evaluated synovial fluid ADA and TB arthritis. The objectives of this study were to determine the proper cut-off level for synovial fluid adenosine deaminase (SF-ADA) and the sensitivity and specificity of SF-ADA to diagnose TB arthritis. Between January 2006 and December 2007, SF-ADA were determined using the modified Giusti's method on patients over 15 years of age with clinically suspected TB arthritis or having an unknown etiology of their arthritis. Synovial fluid culture for TB was performed in all patients as a gold standard test. Forty cases were included in the study, with a female to male ratio of 1.7:1 and a mean age of 52.3 +/- 17.4 years (range, 16-80). The median duration of symptoms was 60 days. The prevalence of TB arthritis was 16.7% (6 cases) while the remaining cases were rheumatoid arthritis (8), non-TB bacterial septic arthritis (3), and miscellaneous (23). The mean SF-ADA levels in patients with TB arthritis and non-TB arthritis were 35.7 +/- 10.4 (range, 20-51) and 15.4 +/- 9 (range, 2-34) U/1, respectively. The cut-off value for the diagnosis of TB arthritis was 31 U/1, with a sensitivity of 83.3% (95% CI 35.9-99.6), a specificity of 96.7% (95% CI 82.8-99.9) and an agreement Kappa of 0.8 (p < 0.001). SF-ADA levels higher than 31 U/1 were highly correlated with a diagnosis of TB arthritis, with a high sensitivity and specificity. SF-ADA may be considered as a less invasive and time-consuming diagnostic tool for TB arthritis.     

Popliteal masses masquerading as popliteal cysts.

Two popliteal swellings, thought initially to be synovial cysts associated with arthritic knees, were found to be unrelated tumours of serious significance. In the presence of neurological signs or a large cyst in association with a noninflammed knee joint a disease other than a simple synovial cyst should be considered.     

The quantitation of a native chondroitin sulfate epitope in synovial fluid lavages and articular cartilage from canine experimental osteoarthritis and disuse atrophy

Objective. Previous studies have shown the presence of a native chondroitin sulfate epitope in articular cartilage proteoglycans from canine knee joints with experimental early osteoarthritis (OA), but not in normal cartilage. The objective of this study was to quantitate the native epitope recognized by monoclonal antibody 3-B-3 in synovial fluids and articular cartilage of diseased joints. Methods. An immunoassay with monoclonal antibody 3-B-3, which recognizes a native chondroitin-6-sulfate structure, was developed and used to analyze synovial fluid lavage material and extracts of articular cartilage from canine knee joints with early experimental OA or with mild disuse atrophy, and from control animals. Results. The concentration of epitope in the OA fluids was elevated 33–35-fold, and in the OA articular cartilage extracts it was elevated > 200-fold, compared with samples from the control group. No significant difference was detected in the levels of 3-B-3 epitope in the synovial fluid lavage material or cartilage extracts from the joints of the disuse group versus the control group. Conclusion. The native 3-B-3 epitope in articular cartilage and synovial fluids may be a specific marker of ongoing anabolic events in early degenerative joint disease.     

Ultrasound guided fine needle aspiration biopsy in mediastinal tuberculosis.

SETTING: Diagnosis of mediastinal tuberculosis (TB) is difficult due to non-specific clinical features and lack of characteristic radiographic features. Histopathological confirmation has often required computed tomography guided fine needle aspiration biopsy (FNAB) or even invasive procedures such as mediastinoscopy or open/surgical biopsy. FNAB under ultrasound (US) guidance can also be performed in this clinical setting. OBJECTIVE: To define the role of percutaneous US guided FNAB in the diagnosis of mediastinal tuberculosis. DESIGN: Twenty-six patients with a proven diagnosis of mediastinal TB formed the study group. Chest radiographs and sputum examination were negative. FNAB was performed via suprasternal (n = 20) and parasternal (n = 6) route under sonographic guidance using 22G spinal needle. Aspirates were considered positive for TB when epithelioid cell granuloma with caseation necrosis and/or the presence of Mycobacterium tuberculosis by acid-fast bacilli (AFB) or culture was demonstrated, indeterminate when epithelioid cell granulomas were seen but without caseation necrosis or AFB, and negative when aspirate contained non-representative material. RESULTS: A total of 30 biopsies were performed in the 26 patients, including repeat biopsy and biopsy of different sites in two patients each. FNAB was positive for TB in 20 of the 26 patients. In four, AFB were demonstrated, and in seven culture was positive for M. tuberculosis; in the remaining six patients, cytologic diagnosis was indeterminate in four and negative in two. No procedure related complications were noted. CONCLUSION: Ultrasound guided FNAB is a safe, effective technique in the diagnosis of mediastinal TB.     

Diagnostic value of blind synovial biopsy in clinical practice

OBJECTIVE: To assess the diagnostic value of blindly performed synovial biopsies in carefully selected patients with unclassified arthritis. METHODS: Synovial tissue was obtained blindly under local anaesthesia. The Arthroforce III take-apart 3.5 mm needle and 1.5 mm grasping forceps were used for this purpose. RESULTS: Four patients with unclassified arthritis could be diagnosed properly based upon examination of synovial tissue of the knee obtained by an easy-to-perform blind biopsy. The arthritis of the four patients was diagnosed as being part of Erdheim-Chester disease, sarcoidosis, multicentric reticulohistiocytosis and arthritis caused by foreign-body material, respectively. CONCLUSIONS: Analysis of synovial tissue obtained during a blind biopsy procedure has diagnostic potential in carefully selected patients with unclassified arthritis. The common denominator in all the cases presented was a differential diagnosis consisting of a rheumatological disease with characteristic histological features.     

Persistence of Staphylococcus aureus as detected by polymerase chain reaction in the synovial fluid of a patient with septic arthritis

Septic arthritis commonly occurs in the rheumatoid arthritis population. The diagnosis is frequently delayed and the associated mortality is high. In this brief report, we present a patient with rheumatoid arthritis and prosthetic knee joints who developed septic arthritis and had persisting evidence of Staphylococcus aureus DNA in synovial fluid, from his knees, which was detected by polymerase chain reaction (PCR) and a gene probe. This was detected until 10 weeks of therapy despite adequate antibiotic treatment and a sterile synovial fluid. In the future, it may be found that PCR of the synovial fluid will be a valuable investigation for the diagnosis and management of septic arthritis.      

Necrotizing non-granulomatous lymphadenitis: a clinicopathologic study of 40 Thai patients

The purpose of this study was to describe the clinicopathological features of 40 cases of necrotizing non-granulomatous lymphadenitis in Thai patients. The clinical features, histomorphology and special stains were evaluated in 40 Thai patients from the pathology records of King Chulalongkorn Memorial Hospital from January 2001 to December 2003 in those diagnosed as having necrotizing non-granulomatous lymphadenitis. Of the 40 patients, 17 cases (42.5%) had Kikuchi-Fujimoto disease (KFD), 8 cases (20%) had tuberculosis (TB) lymphadenitis and 1 case (2.5%) had systemic lupus erythematosus (SLE) with associated lymphadenitis. Fourteen cases (35%) did not have a specific diagnosis due to a lack of follow-up data. KFD most commonly occurs in young women, and is characterized by the presence of coagulative necrosis and karyorrhexis often centered in the paracortex, an absence of neutrophils and plasma cells, proliferation of various cells composed of lymphocytes, histiocytes, immunoblasts and plasmacytoid monocytes and the absence of a granuloma. Tuberculous lymphadenitis usually occurs in women with a mean age of 34.25 years. The lymph nodes reveal extensive coagulative necrosis involving the cortex, paracortex and medulla, proliferation of mixed inflammatory cells, including neutrophils, lymphocytes and plasma cells in the necrotic area and the presence of proliferating histiocytes at the periphery of the necrotic area. The lymph nodes of SLE-associated lymphadenitis reveal large numbers of plasma cells and hematoxylin bodies. We suggest that necrotizing non-granulomatous lymphadenitis is not specific for any disease, but rather a common histologic change found in diseases, such as TB, SLE, and KFD. Further investigation to obtain a definite diagnosis should be done for appropriate treatment.     

Arthritis associated with tuberculosis

There has been a resurgence in tuberculosis (TB) worldwide. Approximately 2 billion people have latent infection, 8 million would develop active TB annually, and 2-3 million would die due to TB. With this resurgence, cases with extrapulmonary TB have also shown an increase. Approximately 10-11% of extrapulmonary TB involves joints and bones, which is approximately 1-3% of all TB cases. The global prevalence of latent joint and bone TB is approximately 19-38 million.TB arthritis most commonly manifests as a monoarthritis of weight-bearing joints in the hip or the knee. Oligo- or polyarticular presentation is not rare and may cause diagnostic confusion with inflammatory arthritis. Owing to the low incidence in developed countries, the diagnosis of joint and bone TB is often delayed. A high degree of sensitivity to this diagnosis would prevent delays, permitting prompt institution of anti-TB therapy and preventing irreversible joint damage. Despite advances, confirmation of diagnosis still relies on lengthy microbiological techniques or invasive biopsy. Due to the frequency of isoniazid resistance, initial treatment at present typically includes a combination of four drugs: isoniazid, rifampicin, pyrazinamide and streptomycin or ethambutol. Antimicrobial therapy should be of at least 9 months duration, longer in children and immunocompromised hosts. Surgical procedures should be restricted to joints with severe cartilage destruction, large abscesses, joint deformity, multiple drug resistance or atypical mycobacteria.     

Intra-articular treatment with the TNF-alpha antagonist, etanercept, in severe diffuse pigmented villonodular synovitis of the knee

Pigmented villonodular synovitis (PVNS) is a rare pre-malignant disease that require aggressive treatment as surgical synovectomy, eventually followed by radiosynovectomy. Nevertheless, the disease often reoccurs after these treatments. To determine the safety and efficacy of intra-articular (IA) TNFalpha blockade with etanercept (ETN), before extended arthroscopic synovectomy, in severe PVNS of the knee, two patients, (a 26-year-old man with B27+ undifferentiated spondylarthropathy and a 32-year-old femal with seronegative oligoarthritis), affected by diffuse knee PVNS (diagnosis made by histological examination), resistant to IA corticosteroid injections and to repeated arthroscopic synovectomy, were submitted, after protocol approval by human research committee and patient's written informed consent to intra-articular etanercept (IA-ETN) treatment with a different dosage schedule: 12.5 mg weekly IA-ETN injection for 4 weeks, followed by extended arthroscopic synovectomy and of 25 mg IA-ETN injection for 4 weeks, respectively. Previous DMARDs treatment was continued in stable appropriate doses. Any adverse events were recorded throughout the study. The following parameters were considered as clinical endpoints: 1) Knee Joint Index (KJI: range 0-14); 2) Thompson index (THI: range 0-9) At the study entry and at the end of follow-up, high frequency ultrasound grey scale synovial thickening (US-ST) was also assessed. No adverse events were observed due to IA-ETN and to arthroscopic synovectomy. Marked improvement of knee disease activity over time and sustained functional recover was obtained. US-ST evaluation before treatment initiation and at the end of follow-up confirmed the regression of knee joint synovial proliferation.     

全膝关节表面置换术治疗结核性膝关节强直或僵硬(附10例报告)

目的 探讨全膝关节表面置换治疗膝关节结核强直或僵硬膝的临床应用可行性。方法 回顾性分析2011年10月至2015年7月我院收治的膝关节结核强直或僵硬膝患者10例,行全膝表面置换术,术前充分评估膝关节功能及结核控制情况,对膝关节结核控制良好,骨缺损不影响假体稳定,无窦道混合感染存在者,行实验室及膝关节MRI、X线、CT扫描等影像学检查,规范化抗结核药物治疗后,行全膝表面置换术,术后继续行正规抗结核药物治疗,随访评估关节假体稳定性、膝关节功能[美国特种外科医院膝关节评分 (hospital for special surgery knee score, 简称 “HSS 评分”)]及关节活动度,关节结核的复发情况。结果 10例患者中,强直膝3例,僵硬膝7例;其中活动期膝关节结核4例,病程4~9个月;陈旧性膝关节结核6例,病程20~41个月;术后全部获24~41个月随访,平均(35.4±9.6)个月;手术时间90~118min,平均(102.0±8.5)min;患者术前膝关节僵硬角度15.0°~55.0°,至末次随访,膝关节屈膝角度恢复至95.0°~120.0°,平均(105.0±14.8)°;伸直角度恢复至-5.0°~10.0°,平均(0.5±7.0)°;术前膝关节HSS评分为(46.6±16.2)分,术后恢复至(79.6±9.6)分。至末次随访,全部假体未见松动,结核无复发。结论 在个体化正规抗结核治疗的前提下,采用普通表面膝关节置换治疗结核性膝关节强直或僵硬疗效确定、临床可行,但需严格掌握手术适应证。     

Outcome of patients with arthritis and parvovirus B19 DNA in synovial membranes

To investigate the follow-up of the 17 patients during the period of 1995–2001 of the outpatient Clinic for Rheumatology at the University Hospital of Zurich with arthritis and the presence of parvovirus B19 DNA demonstrated by PCR in synovial biopsies. Seventeen patients of 163 with arthritis, which were routinely examined by needle arthroscopy during 1995–2001 with a positive parvovirus B19 DNA by PCR of synovial biopsy were reevaluated. Investigations included medical history, clinical examination and blood tests. Joint fluid was taken on patients with joint effusion. The observation period of the 17 patients (F:M = 11:6) was 2–8 years (Ø = 6.5 years). In 8 of 17 patients the arthritis could not be classified neither at entry nor during the follow up of the study. The arthritis could be diagnosed in six patients early in the onset of the disease and included three cases of lyme arthritis of the knee joint, two cases with arthritis following a gastrointestinal infection (one with Salmonella typhimurium—positive faecal test—and the other one with a culture negative agent), one patient probably had an infection-associated arthritis after a gastrointestinal infection with Entamöeba histolytica (Schirmer et al. in Rheumatol Int 18:37–38, 1998; Kasliwal in Am J Proctol Gastroenterol Colon Rectal Surg 32:12, 16, 28, 1981; Haslock and Wright in J R Coll Phys Lond 8:1554–162, 1974; Than-Saw et al. in Trop Geogr Med 44:355–358, 1992) with remission after antibiotic therapy. After a disease course of 9 months one patient could be classified as rheumatoid arthritis in the presence of anti-cyclic citrullinated antibodies but lack of rheumatoid factor. One patient with polyarthritis developed psoriasis of the skin 22 months later. From the nine patients with unclassified arthritis 4 (45%) got into complete remission with no symptoms or signs of joint inflammation after a disease course of 9–45 months, whereas 5 (55%) still demonstrate active non erosive arthritis (disease duration between 3 and 10 years). The presence of parvovirus B19 DNA in synovial tissue of patients with joint inflammation does not allow the diagnosis of parvovirus induced arthritis. If the arthritis remains unclassified and without erosions over time a virus associated aetiology may be assumed. However, no definitive diagnosis is possible even in the presence of parvovirus B19 DNA in synovial tissue.